Summary Hip fractures are the most devastating result of osteoporosis and often the first step in a downward spiral of lost ambulation and independence, institutionalization, and secondary medical morbidity and mortality. Within one year of hip fracture, 50% of patients will be unable to walk without assistance, 25% will require long-term care, and 20% will have died. One potent regulator of bone formation is physical loading (Krahl et al. 1994); however, the cellular sensing mechanism directing mechanotransduction has proven to be elusive. Our laboratory is one of the first to demonstrate that the osteocyte primary cilium plays a major role in this process (Malone et al. 2007). The primary cilium is a solitary cellular extension present in virtually every cell in the body, but its function has yet to be fully characterized. As osteocyte mechanosensors, these organelles act synergistically with other known regulators of bone metabolism. Our contribution is to elucidate the primary cilium microdomain?s role in osteocyte mechanotransduction and identify the intracellular signaling mechanisms involved. This contribution is significant because it catalyzes a continuum of research leading to novel pharmacologic therapeutics that potentiate mechanical loading at a molecular level. The long-term goal of this project is to determine how primary cilia contribute to bone mechanosensing and capitalize on this knowledge to develop novel therapies. The overall objective of this application is to exploit the molecular mechanisms identified in the last funding period to sensitize osteocyte primary cilia and identify osteocyte-cilia specific therapeutic targets. We will achieve this objective by establishing the potential of osteocyte cilia therapeutics in vivo (SA1), enhancing osteocyte-specificity through molecular manipulation of the intraciliary signaling system (SA2), and ensuring that ciliary strategies do not have adverse effects on bone biology (SA3). At the conclusion of this project, we expect to contribute potential pharmacologic agents that target unique characteristics of the osteocyte microdomain to bias bone formation without adverse effects to normal physiology. Osteoporosis prevention will dramatically increase patient quality of life, reduce morbidity, and cut health care costs. A collateral benefit will be extending this knowledge to applications in other cell types to develop treatments for numerous cilia-associated diseases.